Controlled release arginine alpha ketoglutarate

ABSTRACT

An oral formulation of arginine α-ketoglutarate is disclosed which formulation is comprised of arginine α-ketoglutarate and one or more excipient materials. A wide range of different controlled release formulations will be apparent to those skilled in the art upon reading this disclosure. The formulation of arginine α-ketoglutarate and excipient material is designed to obtain a desired result, e.g. attenuate symptoms suffered by a patient with a glutamate dehydrogenase deficiency or increase prolyl hydroxylase and lysyl hydroxylase activity or prevent protein glycation characteristic of atheroscloerosis, cataract formation, retinopathy, and aging. The desired results are obtained by increasing the period of time that a therapeutic level of arginine α-ketoglutarate is continuously maintained in the patient. The therapeutic level as well as the period of time over which that level must be maintained can vary between patient based on a range of factors such as the condition of the patient and the patient&#39;s reactivity to arginine α-ketoglutarate. However, the period of time will be greater than that obtained with a conventional quick release arginine α-ketoglutarate formulation.

CROSS REFERENCES

[0001] This application is a continuation-in-part application of Ser.No. 09/755,890, filed Jan. 5, 2001, which is a continuation-in-part ofearlier filed patent application Ser. No. 09/288,245, filed Apr. 8, 1999now issued U.S. Pat. No. 6,197,340, which is a continuation-in-part ofearlier filed provisional patent application Ser. No. 60/102,605, filedOct. 1, 1998 and patent application Ser. No. 09/112,623, filed Jul. 9,1998, which is the converted patent application of provisional patentapplication Ser. No. 60/087,203, filed May 28, 1998 to which we claimpriority under 35 U.S.C. §120 and §119(e) each of which is incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates generally to a controlled releaseoral formulation of pharmaceutically active compounds. Moreparticularly, the invention relates to controlled release oralformulations of salts of arginine particularly arginine α-ketoglutarate.

BACKGROUND OF THE INVENTION

[0003] Arginine α-ketoglutarate, also known as arginine 2-oxoglutarate,is an organic salt which possesses a number of physiological uses.Studies conducted in 1977 revealed its ability to enhance hepaticdetoxification capacity when administered in high dosage to patientswith liver cirrhosis. (Muting et al. (1977) MMW Munch Med Wochenschr,119(16):535-8.) Its effects were marked by a significant decrease in thelevel of plasma ammonia and free serum phenols, which indicate improvedoxidative decomposition of these compounds. Likewise, administration ofarginine and α-ketoglutarate has also proven useful in treating ammoniaintoxication and heightening liver detoxication in animal models. Notonly was the survival rate found to be higher in the treatment grouprelative to the control, the treatment group also suffered fewerconvulsive episodes.

[0004] In addition, arginine α-ketoglutarate has various uses as asource of α-ketoglutarate. By virtue of its role in the amino acidsynthesis pathway, α-ketoglutarate exerts strong regulatory control overprotein metabolism. Previous studies demonstrated its potency inconserving endogenous glutamine pools and increasing glutaminesynthesis, which have particular benefits in clinical nutrition andmetabolic care by countering trauma-induced catabolism. (Cynober (1999)Curr Opin Clin Nutr Metab Care, 2(l):33-7.) U.S. Pat. No. 5,646,187describes the utility of α-ketoglutarate in treating critically illpatients for improving protein synthesis capacity, preserving lean bodymass and maintaining energy status in skeletal muscle. Similarly, WO89/03688 discloses the use of α-ketoglutarate to increase glutaminecontent in postoperative patients.

[0005] Alpha-ketoglutarate also possesses antioxidative properties, assupported by studies on hydrogen peroxide (H₂O₂)-induced hemolysis ofhuman erythrocytes. The non-enzymatic oxidative decarboxylation ofalpha-keto acids is shown to be involved in the hydrogen peroxidedecomposition process. As part of the pathway leading to the citric acidcycle, α-ketoglutarate is crucial to energy generation. Studies in thisarea have yielded a significant correlation between leukocyte glutamatedehydrogenase deficiency and the presence of extrapyramidal signs,supranuclear palsy, absence of osteotendineal reflexes and neurogenicelectromyographical findings. (Orsi et al. (1988) Acta Neurol Scand,78(5):394-400.)

[0006] Furthermore, there is a significant link between geneticdeficiency of glutamate dehydrogenase, an enzyme which convertsglutamate to α-ketoglutarate, and certain dominantly inherited ataxiasand olivopontocerebellar atrophy (OPCA). (Plaitakis et al. (1980) AnnNeurol, 7(4):297-303, Chokroverty et al. (1985) Neurology, 35(5):652-9.)Ataxia is a condition characterized by failure of motor control and/orirregularity of muscular action whereas OPCA refers to a group ofataxias characterized by progressive neurological degeneration affectingthe cerebellum, the pons and the inferior olives.

[0007] In collagen synthesis, α-ketoglutarate plays an important role asone of the cofactors of prolyl hydroxylase and lysyl hydroxylase,enzymes responsible for hydroxylation of proline and lysine residues.Studies conducted on scorbutic animal models which characteristicallyexhibit lowered prolyl hydroxylase activity indicate that the enzymeactivity could be increased by incubating homogenates with ascorbate(Vitamine C), ferrous ions, and α-ketoglutarate thereby alleviating thepathological symptoms. (Kuttan (1980) J Nutr, 110(8):1525-32.)

[0008] Alpha-ketoglutarate is also highly effective in preventingglycosylation/glycation of proteins associated with diabeticcomplications such as atherosclerosis, cataract formation, andretinopathy, and mere aging. Protein-bound advanced glycationendproducts (AGEs) can exert cytotoxic effects on neighboring cells andare, for example, the structural components of beta-amyloid plaques inAlzheimer's disease. Administration of α-ketoglutarate, however,attenuates the cytotoxicity of these AGEs via the compound's competitiveinhibition of protein glycation and antioxidant properties. In the caseof diabetic retinopathy, even careful monitoring of blood glucose levelsdoes not necessarily preclude pathogenesis. Therefore, the intake ofα-ketoglutarate is required in addition to a diabetic drug to preventthe glycation process in retinopathy.

SUMMARY OF THE INVENTION

[0009] An oral formulation of arginine α-ketoglutarate is disclosedwhich formulation is comprised of arginine α-ketoglutarate and one ormore excipient materials. A wide range of different controlled releaseformulations will be apparent to those skilled in the art upon readingthis disclosure. The formulation of arginine α-ketoglutarate andexcipient material is designed to obtain a desired result, e.g.attenuate symptoms suffered by a patient with a glutamate dehydrogenasedeficiency or increase prolyl hydroxylase and lysyl hydroxylase activityor prevent protein glycation characteristic of atheroscloerosis,cataract formation, retinopathy, and aging. The desired results areobtained by increasing the period of time that a therapeutic level ofarginine α-ketoglutarate is continuously maintained at a desiredtherapeutic level in the patient. The therapeutic level as well as theperiod of time over which that level must be maintained can vary betweenpatient based on a range of factors such as the condition of the patientand the patient

s reactivity to arginine α-ketoglutarate. However, the period of timewill be greater than that obtained with a conventional quick releasearginine α-ketoglutarate formulation.

[0010] The ratio of arginine α-ketoglutarate to excipient material andthe particular excipients used result in a formulation which allows thearginine α-ketoglutarate to be released in a controlled manner forabsorption into the circulatory system. By maintaining a desired serumlevel of arginine α-ketoglutarate in blood serum the oral formulation ofthe invention achieves physiological effects which are superior to thosewhich might be obtained when higher serum levels are obtained for ashort term with a quick release oral dosage formulation or a single doseinjectable formulation.

[0011] By providing for controlled release of arginine α-ketoglutaratethe physiological effects are continually provided over a period of timeresulting in obtaining a range of associated health benefits. Thecontrolled release formulation of the invention shows that highlydesirable therapeutic effects can be obtained by maintaining atherapeutic arginine α-ketoglutarate blood serum level over a period oftime which is meaningfully longer than that obtained with a quickrelease formulation and results are improved by maintaining such dayafter day. A formulation of the invention will preferably maintaintherapeutic levels of arginine α-ketoglutarate over a period which is10% or more, more preferably 50% or more and still more preferably 100%or more than the period of time maintained by a quick releaseformulation.

[0012] To obtain a particularly preferred result, the oral formulationof the invention will quickly release a sufficient amount of arginineα-ketoglutarate so as to quickly obtain a therapeutic level andthereafter release arginine α-ketoglutarate at a rate whichsubstantially matches the rate at which the arginine α-ketoglutarate isbeing metabolized. Accordingly, the formulation is designed to maintaina therapeutic level over a maximum amount of time based on the amount ofarginine α-ketoglutarate in the formulation and to not significantlyexceed the therapeutic level.

[0013] An aspect of the invention is an oral formulation of arginineα-ketoglutarate, and excipient compounds which provide for controlledrelease.

[0014] A more specific aspect of the invention is that the formulationprotects arginine α-ketoglutarate from degradation and allows it to beslowly released over time.

[0015] An advantage of the invention is that by maintaining relativelylow serum levels of arginine α-ketoglutarate over long periods of time,protein glycation can be inhibited, thereby preventing the onset ofatherosclerosis, cataracts, retinopathy, and adverse effects of aging.

[0016] Another advantage of the invention is that by administering theformulation over longer periods, the patient is provided with a reducedrisk of developing atherosclerosis, diseases of the eye and adverseconditions associated with aging.

[0017] Another aspect of the invention is that the formulation providesa method of enhancing prolyl hydroxylase and lysyl hydroxylase activity.

[0018] Yet another aspect of the invention is that the formulationprovides a method of treating symptoms of dominant ataxias arising fromglutamate dehydrogenase deficiency.

[0019] An advantage of the invention is that a convenient oral deliverydosage form is used to obtain the results which are superior to a singleinjectable dose.

[0020] A feature of the invention is that the oral formulation may be atablet, capsule, caplet, etc. comprising a controlled release excipientand any desired amount of arginine α-ketoglutarate.

[0021] Another aspect of the invention is that it may be formulated withone or more additional prolyl and lysyl hydroxylase cofactors, e.g.,ascorbic acid and iron donors.

[0022] Another aspect of the invention is a method of treatment wherebysustained low levels of arginine α-ketoglutarate blood serum over longperiods continually stimulate basal prolyl hydroxylase and lysylhydroxylase activity.

[0023] These and other objects, aspects, advantages, and features of theinvention will become apparent to those persons skilled in the art uponreading the details of the invention as more fully described below.

DETAILED DESCRIPTION OF THE INVENTION

[0024] Before the present, formulations, methods and components usedtherein are disclosed and described, it is to be understood that thisinvention is not limited to particular compounds, excipients orformulations as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

[0025] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

[0026] The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided are subject to change if itis found that the actual date of publication is different from thatprovided here.

DEFINITIONS

[0027] The term “arginine α-ketoglutarate” is intended to mean arginineα-ketoglutarate which is a salt also known as arginine 2-ketoglutarate,arginine 2-oxoglutamate, and arginine 2-oxopentanedioic acid. Unlessspecified, the term covers the racemic mixture as well as any other(non-50/50) mixture of the enantiomers including substantially pureforms of either the R-(+) or the S-(−) enantiomer. Further, unlessspecified otherwise the term covers pharmaceutically acceptable salts(e.g. Na and K salts) and amides, esters and metabolites of the acid. Inreferring to pharmaceutically acceptable salts the term is intended toencompass a conventional term of pharmaceutically acceptable acidaddition salts which refer to salts which retain the biologicaleffectiveness and properties of the free-base form of the acid and whichare not biologically or otherwise undesirable, formed with inorganicacids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid and the like, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malicacid, malconic acid, succinic acid, maleic acid, fumaric, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid andthe like. The same is true with respect to amides, esters andmetabolites that is those forms which can be formed and maintainbiological effectiveness and not have significant undesirable biologicalproperties.

[0028] The term “excipient material” is intended to mean any compoundforming a part of the formulation which is intended to act merely as acarrier, i.e., not intended to have biological activity itself.

[0029] The term “chemical degradation” is intended to mean that thearginine α-ketoglutarate active ingredient is subjected to a chemicalreaction which disrupts its biological activity.

[0030] The terms “treating” and “treatment” and the like are used hereinto generally mean obtaining a desired pharmacological and physiologicaleffect. The effect may be prophylactic in terms of preventing orpartially preventing a disease, symptom or condition thereof and/or maybe therapeutic in terms of a partial or complete cure of a disease,condition, symptom or adverse effect attributed to the disease. The term“treatment” as used herein covers any treatment of a disease in amammal, particularly a human, and includes: (a) preventing the diseasefrom occurring in a subject which may be predisposed to the disease buthas not yet been diagnosed as having it; (b) inhibiting the disease,i.e., arresting its development; or (c) relieving the disease, i.e.,causing regression of the disease and/or its symptoms or conditions. Theinvention is directed towards treating patient's symptoms from glutamatedehydrogenase deficiency and depressed prolyl hydroxylase and lysylhydroxylase activity. The present invention is involved in preventing,inhibiting, or relieving adverse effects attributed to glycation ofproteins characteristic of atherosclerosis, cataract formation,retinopathy, and aging.

[0031] The term “quick release formulation” refers to a conventionaloral dosage formulation. Such a formulation may be a tablet, capsule orthe like designed to provide for substantially immediate release of theactive ingredient and includes enteric coated oral formulation whichprovide some initial protection to the active ingredient and thereafterallow substantially immediate release of substantially all the activeingredient. A quick release formulation is not formulated in a manner soas to obtain a gradual, slow, or controlled release of the activeingredient.

FORMULATION IN GENERAL

[0032] The formulation of the invention is preferably an oral dosageformulation which may be in any suitable oral form including tablets,capsules, caplets, suspensions, etc. The dosage may be of any desiredsize in terms of the arginine α-ketoglutarate active ingredient.However, sizes in a range of about 50 mg to about 1,000 mg are generallyused, and are preferably in the range of about 100 mg to about 500 mgand more preferably about 300 mg. The amount a patient will need toobtain an optimum therapeutical effect will vary with a number offactors known to those skilled in the art, e.g., the size, age, weight,sex and condition of the patient. The patient may begin with daily dosesof about 300 mg and determine, for example, if the effects of glutamatedehydrogenase deficiency has been offset. If the desired results are notobtained in one week, the daily dosage amount can be increased inincrements of 100 to 300 mg/day up to any useful amount, e.g., 2,000mg/day. A suggested dosage is to administer two 300 mg tablets in themorning and administer one 300 mg tablet four hours later and repeatdaily over five or more days. The larger initial dosage has been foundeffective in obtaining a desired effect which after being obtained canbe maintained by a lower dose. Thus, a biological system may be “kickstarted” by a high therapeutic level and then maintained at a lowerlevel which is also therapeutic in terms of obtaining a desired result.

[0033] A typical formulation contains about 50-70% by weight arginineα-ketoglutarate active ingredient with the remainder being excipientmaterial. Preferably the formulation comprises 55% to 65% activeingredient and more preferably about 60% active ingredient by weight.Thus, a particularly preferred oral formulation of the inventioncomprises about 300 mg of arginine α-ketoglutarate and about 200 mg ofexcipient material. Human patients generally eat during the day andsleep at night. Eating causes increased glucose levels. Accordingly, itis generally preferable to give a larger dose of arginineα-ketoglutarate at the beginning of the day. This may include two 300 mgtablets or a single 600 mg tablet. Later in the day (about 4 hourslater) the patient will take an additional 300 mg for a typical dailydose of about 900 mg for a 70 kg man.

[0034] The formulation is characterized by (a) protecting the activeingredient from chemical degradation in a patient's gastrointestinaltract and (b) releasing the active ingredient in a controlled manner. Bygradually releasing the active ingredient, the serum levels of arginineα-ketoglutarate obtained are (1) lower than those obtained with singleinjectable dose or a non-controlled release formulation; and (2)maintained over longer periods of time at a therapeutic level thanobtained with single injectable dose or a non-controlled releaseformulation. Specifically, a formulation of the invention releasesactive ingredient so as to obtain a blood serum level in a human patientin a range of about 25 to about 75 ng/ml of plasma. The range ispreferably about 35 to about 65 ng/ml of plasma and more preferablyabout 50 ng/ml of plasma ±5%.

[0035] Arginine α-ketoglutarate is characterized as (1) non-toxic atrelatively high levels, i.e., levels well in excess of therapeuticlevels; and (2) quickly metabolized by human patients. The presentinvention relies in part on the discovery that arginine α-ketoglutarateprovides desirable therapeutic results even at very low levels providedthose low levels are maintained over an extended period of time; whereastherapeutic results are not obtained (even with higher levels) if thetherapeutic level is not maintained over a sufficient period of time.Further, the present invention relies in part on the discovery thattherapeutic results are further improved if the formulation is deliveredover a period of five or more days, preferably thirty or moreconsecutive days with long periods of therapeutic levels of arginineα-ketoglutarate being obtained on each of the days.

[0036] One aspect of the invention is that a range of highly desirabletherapeutic effects are obtained even when the arginine α-ketoglutarateblood serum levels are maintained in a range well below those previousused. The present invention could obtain desired therapeutics effectswith higher levels of arginine α-ketoglutarate in blood serum. However,at least minimum levels would need to be constantly maintained over along period of time (4 hours or more per day) for a plurality of days toobtain the desired results. When the oral dosage form is designed toobtain the lowest possible therapeutic level over the longest possibletime period the results obtained are maximized and the amount of drugneeded is minimized.

[0037] The arginine α-ketoglutarate blood plasma level obtained via thepresent invention is insufficient to obtain a desired therapeutic effectif that level is maintained for only a short period of time, e.g., 4hours or less. However, by using the controlled release formulation ofthe invention these lower arginine α-ketoglutarate blood plasma levelscan be maintained over 8 hours or more, preferably over 12 hours or moreand more preferably over 16 hours or more per day. Further, thosearginine α-ketoglutarate blood plasma levels over these periods of timeare repeatedly obtained over a period of days, preferably weeks ormonths and more preferably continuously over any period during which thepatient would benefit from, for example, the substance's inhibition ofprotein glycation—which may be the remainder of the patient's life.

[0038] To obtain the desired results, a formulation of the inventionincludes a sufficient amount of arginine α-ketoglutarate such that it iscapable of releasing enough arginine α-ketoglutarate per unit of time toobtain the desired arginine α-ketoglutarate serum levels whilecompensating for arginine α-ketoglutarate which is metabolized. Toobtain the desired results the formulation may immediately and quicklyprovide an initial release of arginine α-ketoglutarate and thereafterprovide a gradual release which slows over the useful life of theformulation. However, the release may be gradual from the beginning. Ineither case, there is a gradual slowing of the rate of release which iscompensated for in that some of the previously released arginineα-ketoglutarate remains in the blood serum unmetabolized.

[0039] A preferred oral formulation is a tablet which is designed todissolve gradually over a period of about 8 hours. As the tabletdissolves, its reduced size will release smaller and smaller amounts ofarginine α-ketoglutarate per unit of time. However, because theindividuals system already contains a therapeutic level of arginineα-ketoglutarate, the slower release rate is sufficient to match the rateof arginine α-ketoglutarate being metabolized and such will result inmaintaining a relatively constant therapeutic level. At the end of thetime when release of arginine α-ketoglutarate is no longer taking place(e.g., about 4 to 8 hours), another tablet is administered and theprocess is repeated. To obtain the benefits of the invention, theprocess is continually repeated over a plurality of days, weeks, monthsor years. By maintaining a minimal arginine α-ketoglutarate blood serumlevel over time, a patient's symptoms arising from a genetic glutamatedehydrogenase deficiency and depressed prolyl hydroxylase and lysylhydroxylase activity would be alleviated. Likewise, those patients atincreased risk for atherosclerosis, cataract formation, and retinopathywould have lowered their chances of pathogenesis.

EXCIPIENT MATERIAL

[0040] Examples provided here show that formulations of the inventionmay comprise different amounts and ratios of active ingredient andexcipient material. Further, different excipients can be used.Particularly preferred excipients and amounts used are recited in theExamples. However, upon reading the disclosure those skilled in the artwill come to understand the general concepts of the invention and willrecognize that other excipients, amounts, ratios and combinations mightbe used to obtain the results first shown here.

[0041] The type and amount of excipient material is added to obtain aformulation having certain characteristics. First, the resultingformulation protects the active ingredient from chemical degradation inthe patient's gastrointestinal tract. A formulation of pure, unprotectedarginine α-ketoglutarate is not part of the scope of the presentinvention in that pure arginine α-ketoglutarate is degraded to somedegree in the gastrointestinal tract. Although the formulation need notprotect 100% of the arginine α-ketoglutarate from degradation to comewithin the scope of the invention, it should protect at least 90% ormore, preferably 95% or more and more preferably 99% or more of thearginine α-ketoglutarate from degradation. Although multiple doses of anoral formulation could be taken it is preferable to design the dosagesuch that a single dose is taken at each dosing event—preferably threetimes a day and more preferably twice a day. The better the activeingredient is protected from degradation the less active ingredient isneeded in the original dosage thereby reducing manufacturing costs andincreasing profits. The formulation must protect at least as much of thedose as is needed to obtain a pharmacological effect and preferablyobtain the desired treatment results, e.g., maintaining a desiredarginine α-ketoglutarate serum level needed to compensate for geneticglutamate dehydrogenase deficiency.

[0042] Another characteristic of the formulation is that it does notrelease all of the active ingredient at one time but rather releases theactive ingredient gradually over time at a controlled rate of releasewhich rate is preferably constant over 4 hours or more. This isparticularly important because a desired level of arginineα-ketoglutarate in blood serum must be maintained over a long period toobtain the desired effect. If all of the arginine α-ketoglutarate isreleased at once, it will all enter the circulatory system at once andbe metabolized in the liver thereby causing the arginine α-ketoglutarateserum level to drop below the desired level. When this occurs, thecompensation for glutamate dehyrogenase deficiency would be suboptimal.

TYPICAL FORMULATIONS

[0043] A typical formulation of the invention will contain about 50% toabout 70% by weight of arginine α-ketoglutarate and a particularlypreferred formulation will comprise 60% by weight of arginineα-ketoglutarate. Assuming a formulation with about 50 to about 66.7% byweight of arginine α-ketoglutarate with the remaining being excipientmaterial, there are a number of possible components which could be usedto make up the remainder of the formulation A generalized and specificdescription of such is provided below:  (1) arginine α-ketoglutarate 60%organic polymer 40% TOTAL 100%  (2) arginine α-ketoglutarate 60% organicpolymer 34.5% inorganics 5.5% TOTAL 100%  (3) arginine α-ketoglutarate60% organic polymer 30%-40% inorganics 10% or less TOTAL 100%  (4)arginine α-ketoglutarate 60% microcrystalline cellulose 14% celluloseacetate phthalate aqueous dispersion 15% polyvinylpyraolidone 3% ethylacetate 2.5% hydrous magnesium silicate (talc) 1% carboxy methyl ether4% magnesium stearate 0.5% TOTAL 100%  (5) arginine α-ketoglutarate 60%microcrystalline cellulose 10-30% cellulose acetate phthalate aqueousdispersion 5-25% polyvinylpyraolidone 1-5% ethyl acetate 1-5% hydrousmagnesium silicate (talc) 0.5-3% carboxy methyl ether 1-5% magnesiumstearate 0.5-1.5% TOTAL 100%  (6) arginine α-ketoglutarate 60%microcrystalline cellulose, NF (Avicel PH 101) 14% Aquacoat CPD-30 (30%solids w/w) 15% Plasdone K29/32, USP 3% Carbopol 974P, NF 2.5% Talc, USP1.0% croscarmellose sodium, NF (Ac, di-Sol) 4.0% Magnesium Stearate, NF0.5% TOTAL 100%  (7) arginine α-ketoglutarate 60% microcrystallinecellulose, NF (Avicel PH 101) 10-30% Aquacoat CPD-30 (30% solids w/w)5-25% Plasdone K29/32, USP 1-5% Carbopol 974P, NF 1-5% Talc, USP 0.5-3%croscarmellose sodium, NF (Ac, di-Sol) 1-5% Magnesium Stearate, NF0.5-1.5% TOTAL 100%  (8) arginine α-ketoglutarate 67% Di-CalciumPhosphate 15.1% Zein 2.1% Pectin 4% Glycerin 6.5% Alginate (Satialgine)3.3% PVAP 2% TOTAL 100%  (9) arginine α-ketoglutarate 60%Poly-DL-lactide-co-glycolide (PLG) 40% TOTAL 100% (10) arginineα-ketoglutarate 60% hydroxypropyl methylcellulose 30% Spray-driedlactose 9.5% Magnesium stearate 0.5% TOTAL 100% (11) arginineα-ketoglutarate 60-65% hydroxypropyl methylcellulose 20-30% lactose5-15% microcrystalline cellulose 4-6% titanium dioxide 1-5% TOTAL 100%(12) arginine α-ketoglutarate 60% hydroxypropylcellulose 40% TOTAL 100%(13) arginine α-ketoglutarate 60% hydroxypropylcellulose 30%polyethylene oxide 10% TOTAL 100% (14) arginine α-ketoglutarate 60%hydroxypropylcellulose 15% hydroxypropyl methylcellulose 25% TOTAL 100%(15) arginine α-ketoglutarate 65% hydroxypropyl methycellulose 40%dibasic calcium phosphate 6% colloidal silicon dioxide 4% TOTAL 100%(16) arginine α-ketoglutarate 50-55% hydroxyalkylcellulose 20-40%lactose 5-15% microcrystalline cellulose 4-6% titanium dioxide 1-5%TOTAL 100% (17) arginine α-ketoglutarate 60% alkylcellulose 30%spray-dried lactose 9.5% magnesium stearate 0.5% TOTAL 100% (18)arginine α-ketoglutarate 60% carboxymethylcellulose (hydrogel matrix)10% polyethylene oxide (hydrogel matrix) 30% TOTAL 100% (19) arginineα-ketoglutarate 60% polyvinylpyrrolidone (hydrogel matrix) 15%polyethylene glycol (hydrogel matrix) 25% TOTAL 100% (20) arginineα-ketoglutarate 50-55% hydroxypropyl methylcellulose 10-20%ethylcellulose 10-20% lactose 5-15% sorbitol 4-6% silicon dioxide 1-5%TOTAL 100% (21) arginine α-ketoglutarate 50% cellulose acetate butyrate30% starch 9.5% magnesium stearate 0.5% TOTAL 100% (22) arginineα-ketoglutarate 50% cellulose acetate phthalate 30% cellulose acetatetrimellitate 10% mannitol 9.5% calcium stearate 0.5% TOTAL 100% (23)arginine α-ketoglutarate 50% polyvinylacetate phthalate 35%hydroxypropylmethylcelluulose phthalate 5% sucrose 5-9% stearic acid1-5% TOTAL 100% (24) arginine α-ketoglutarate 50% methylcellulose 35%hydroxypropylmethylcellulose 5% glucose 4% talc 0.5% PEG 6000 0.5% TOTAL100% (25) arginine α-ketoglutarate 60% polyethylene glycol 20%poly(alkyl methacrylate) 10% calcium stearate 5% dibasic calciumphosphate 3% poloxamers 2% TOTAL 100% (26) arginine -ketoglutarate 60%Hydroxypropylmethylcellulose 24% Pectin 12% magnesium stearate 4% TOTAL100% (27) arginine -ketoglutarate 66.7% calcium sulfate 17.3% zein 1.3%alginate 3.3% pectin 4.0% glycerin 6.7% magnesium stearate 0.7% TOTAL100%

[0044] Those skilled in the art will recognize that there are endlesspossibilities in terms of formulations and that a margin of error e.g.,±20% or more preferably ±10%, should be accounted for with eachcomponent. Even if the formulations are limited to the relatively fewcompounds shown above, the formulation could be changed in limitlessways by adjusting the ratios of the components to each other. Theimportant feature of any formulation of the invention is that thearginine α-ketoglutarate be released in a controlled manner which makesit possible to maintain therapeutic levels of arginine α-ketoglutarateover a substantially longer period of time as compared to a quickrelease formulation. A particularly preferred formulation will quicklyobtain a therapeutic level and thereafter decrease the rate of releaseto closely match the rate at which arginine α-ketoglutarate is beingmetabolized thereby maintaining a therapeutic level in the patient overa maximum period of time based on the amount of arginine α-ketoglutaratein the oral dosage formulation. Some general types of controlled releasetechnology which might be used with the present invention are describedbelow followed by specific preferred formulations.

CONTROLLED RELEASE TECHNOLOGY

[0045] Controlled release within the scope of this invention can betaken to mean any one of a number of extended release dosage forms. Thefollowing terms may be considered to be substantially equivalent tocontrolled release, for the purposes of the present invention:continuous release, controlled release, delayed release, depot, gradualrelease, long-term release, programmed release, prolonged release,proportionate release, protracted release, repository, retard, slowrelease, spaced release, sustained release, time coat, timed release,delayed action, extended action, layered-time action, long acting,prolonged action, repeated action, slowing acting, sustained action,sustained-action medications, and extended release. Further discussionsof these terms may be found in Lesczek Krowczynski, Extended-ReleaseDosage Forms, 1987 (CRC Press, Inc.).

[0046] There are companies with specific expertise in drug deliverytechnologies including controlled release oral formulations such as AlzaCorporation and Elan Pharmaceuticals, Inc.. A search of patents,published patent applications and related publications will providethose skilled in the art reading this disclosure with significantpossible controlled release oral formulations. Examples include theformulations disclosed in any of the U.S. Pat. Nos. 5,637,320 issuedJun. 10, 1997; 5,505,962 issued Apr. 9, 1996; 5,641,745 issued Jun. 24,1997; and 5,641,515 issued Jun. 24, 1997. Although specific formulationsare disclosed here and in these patents, the invention is more generalthan any specific formulation. This includes the discovery that byplacing arginine α-ketoglutarate in a controlled release formulationwhich maintains therapeutic levels over substantially longer periods oftime, as compared to quick release formulations, improved unexpectedresults are obtained.

[0047] The various controlled release technologies cover a very broadspectrum of drug dosage forms. Controlled release technologies include,but are not limited to physical systems and chemical systems.

[0048] Physical systems include, but are not limited to, reservoirsystems with rate-controlling membranes, such as microencapsulation,macroencapsulation, and membrane systems; reservoir systems withoutrate-controlling membranes, such as hollow fibers, ultra microporouscellulose triacetate, and porous polymeric substrates and foams;monolithic systems, including those systems physically dissolved innon-porous, polymeric, or elastomeric matrices (e.g., nonerodible,erodible, environmental agent ingression, and degradable), and materialsphysically dispersed in non-porous, polymeric, or elastomeric matrices(e.g., nonerodible, erodible, environmental agent ingression, anddegradable); laminated structures, including reservoir layers chemicallysimilar or dissimilar to outer control layers; and other physicalmethods, such as osmotic pumps, or adsorption onto ion-exchange resins.

[0049] Chemical systems include, but are not limited to, chemicalerosion of polymer matrices (e.g., heterogeneous, or homogeneouserosion), or biological erosion of a polymer matrix (e.g.,heterogeneous, or homogeneous). Additional discussion of categories ofsystems for controlled release may be found in Agis F. Kydonieus,Controlled Release Technologies: Methods, Theory and Applications, 1980(CRC Press, Inc.).

[0050] Controlled release drug delivery systems may also be categorizedunder their basic technology areas, including, but not limited to,rate-preprogrammed drug delivery systems, activation-modulated drugdelivery systems, feedback-regulated drug delivery systems, andsite-targeting drug delivery systems.

[0051] In rate-preprogrammed drug delivery systems, release of drugmolecules from the delivery systems “preprogrammed” at specific rateprofiles. This may be accomplished by system design, which controls themolecular diffusion of drug molecules in and/or across the barriermedium within or surrounding the delivery system. Fick's laws ofdiffusion are often followed.

[0052] In activation-modulated drug delivery systems, release of drugmolecules from the delivery systems is activated by some physical,chemical or biochemical processes and/or facilitated by the energysupplied externally. The rate of drug release is then controlled byregulating the process applied, or energy input.

[0053] In feedback-regulated drug delivery systems, release of drugmolecules from the delivery systems may be activated by a triggeringevent, such as a biochemical substance, in the body. The rate of drugrelease is then controlled by the concentration of a triggering agentdetected by a sensor in the feedback regulated mechanism.

[0054] In a site-targeting controlled-release drug delivery system, thedrug delivery system targets the active molecule to a specific site ortarget tissue or cell. This may be accomplished, for example, by aconjugate including a site specific targeting moiety that leads the drugdelivery system to the vicinity of a target tissue (or cell), asolubilizer that enables the drug delivery system to be transported toand preferentially taken up by a target tissue, and a drug moiety thatis covalently bonded to the polymer backbone through a spacer andcontains a cleavable group that can be cleaved only by a specific enzymeat the target tissue.

[0055] While a preferable mode of controlled release drug delivery willbe oral, other modes of delivery of controlled release compositionsaccording to this invention may be used. These include mucosal delivery,nasal delivery, ocular delivery, transdermal delivery, parenteralcontrolled release delivery, vaginal delivery, and intrauterinedelivery.

[0056] There are a number of controlled release drug formulations thatare developed preferably for oral administration. These include, but arenot limited to, osmotic pressure-controlled gastrointestinal deliverysystems; hydrodynamic pressure-controlled gastrointestinal deliverysystems; membrane permeation-controlled gastrointestinal deliverysystems, which include microporous membrane permeation-controlledgastrointestinal delivery devices; gastric fluid-resistant intestinetargeted controlled-release gastrointestinal delivery devices; geldiffusion-controlled gastrointestinal delivery systems; andion-exchange-controlled gastrointestinal delivery systems, which includecationic and anionic drugs. Additional information regarding controlledrelease drug delivery systems may be found in Yie W. Chien, Novel DrugDelivery Systems, 1992 (Marcel Dekker, Inc.). Some of these formulationswill now be discussed in more detail.

[0057] Enteric coatings are applied to tablets to prevent the release ofdrugs in the stomach either to reduce the risk of unpleasant sideeffects or to maintain the stability of the drug which might otherwisebe subject to degradation due to exposure to the gastric environment.Most polymers that are used for this purpose are polyacids that functionby virtue or the fact that their solubility in aqueous medium ispH-dependent, and they require conditions with a pH higher then thatwhich is normally encountered in the stomach.

[0058] One preferable type of oral controlled release structure isenteric coating of a solid or liquid dosage form. Enteric coatingspromote the lipoates' remaining physically incorporated in the dosageform for a specified period when exposed to gastric juice. Yet theenteric coatings are designed to disintegrate in intestinal fluid forready absorption. Delay of the lipoates' absorption is dependent on therate of transfer through the gastrointestinal tract, and so the rate ofgastric emptying is an important factor. Some investigators havereported that a multiple-unit type dosage form, such as granules, may besuperior to a single-unit type. Therefore, in a preferable embodiment,the lipoates may be contained in an enterically coated multiple-unitdosage form. In a more preferable embodiment, the lipoate dosage form isprepared by spray-coating granules of a lipoate-enteric coating agentsolid dispersion on an inert core material. These granules can result inprolonged absorption of the drug with good bioavailability.

[0059] Typical enteric coating agents include, but are not limited to,hydroxypropylmethylcellulose phthalate, methacryclic acid-methacrylicacid ester copolymer, polyvinyl acetate-phthalate and cellulose acetatephthalate. Akihiko Hasegawa, Application of solid dispersions ofNifedipine with enteric coating agent to prepare a sustained-releasedosage form, Chem. Pharm. Bull. 33: 1615-1619 (1985). Various entericcoating materials may be selected on the basis of testing to achieve anenteric coated dosage form designed ab initio to have a preferablecombination of dissolution time, coating thicknesses and diametralcrushing strength. S. C. Porter et al., The Properties of Enteric TabletCoatings Made From Polyvinyl Acetate-phthalate and Cellulose acetatePhthalate, J. Pharm. Pharmacol. 22:42p (1970).

[0060] On occasion, the performance of an enteric coating may hinge onits permeability. S. C. Porter et al., The Permeability of EntericCoatings and the Dissolution Rates of Coated Tablets, J. Pharm.Pharmacol. 34: 5-8 (1981). With such oral drug delivery systems, thedrug release process may be initiated by diffusion of aqueous fluidsacross the enteric coating. Investigations have suggested osmoticdriven/rupturing affects as important release mechanisms from entericcoated dosage forms. Roland Bodmeier et al., Mechanical Properties ofDry and Wet Cellulosic and Acrylic Films Prepared from Aqueous ColloidalPolymer Dispersions used in the Coating of Solid Dosage Forms,Pharmaceutical Research, 11: 882-888 (1994).

[0061] Another type of useful oral controlled release structure is asolid dispersion. A solid dispersion may be defined as a dispersion ofone or more active ingredients in an inert carrier or matrix in thesolid state prepared by the melting (fusion), solvent, ormelting-solvent method. Akihiko Hasegawa, Super Saturation Mechanism ofDrugs from Solid Dispersions with Enteric Coating Agents, Chem. Pharm.Bull. 36: 4941-4950 (1998). The solid dispersions are also referred toas solid-state dispersions. The term “coprecipitates” may also be usedto refer to those preparations obtained by the solvent methods.

[0062] Solid dispersions may be used to improve the solubilities and/ordissolution rates of poorly water-soluble lipoates. Hiroshi Yuasa, etal., Application of the Solid Dispersion Method to the ControlledRelease Medicine. III. Control of the Release Rate of SlightlyWater-Soluble Medicine From Solid Dispersion Granules, Chem. Pharm.Bull. 41:397-399 (1993). The solid dispersion method was originally usedto enhance the dissolution rate of slightly water-soluble medicines bydispersing the medicines into water-soluble carriers such aspolyethylene glycol or polyvinylpyraolidone, Hiroshi Yuasa, et al.,Application of the Solid Dispersion Method to the Controlled Release ofMedicine. IV. Precise Control of the Release Rate of a Water-SolubleMedicine by Using the Solid Dispersion Method Applying the Difference inthe Molecular Weight of a Polymer, Chem. Pharm. Bull. 41:933-936 (1993).

[0063] The selection of the carrier may have an influence on thedissolution characteristics of the dispersed drug because thedissolution rate of a component from a surface may be affected by othercomponents in a multiple component mixture. For example, a water-solublecarrier may result in a fast release of the drug from the matrix, or apoorly soluble or insoluble carrier may lead to a slower release of thedrug from the matrix. The solubility of the lipoates may also beincreased owing to some interaction with the carriers.

[0064] Examples of carriers useful in solid dispersions according to theinvention include, but are not limited to, water-soluble polymers suchas polyethylene glycol, polyvinylpyraolidone, orhydroxypropylmethyl-cellulose. Akihiko Hasegawa, Application of SolidDispersions of Nifedipine with Enteric Coating Agent to Prepare aSustained-release Dosage Form, Chem. Pharm. Bull. 33: 1615-1619 (1985).

[0065] Alternate carriers include phosphatidylcholine. Makiko Fujii, etal., The Properties of Solid Dispersions of Indomethacin, Ketoprofen andFlurbiprofen in Phosphatidylcholine, Chem. Pharm. Bull. 36:2186-2192(1988). Phosphatidylcholine is an amphoteric but water-insoluble lipid,which may improve the solubility of otherwise insoluble lipoates in anamorphous state in phosphatidylcholine solid dispersions. See MakikoFujii, et al., Dissolution of Bioavailibility of Phenytoin in SolidDispersion with Phosphatidylcholine, Chem. Pharm. Bull 36:4908-4913(1988).

[0066] Other carriers include polyoxyethylene hydrogenated castor oil.Katsuhiko Yano, et al., In-Vitro Stability and In-Vivo AbsorptionStudies of Colloidal Particles Formed From a Solid Dispersion System,Chem. Pharm. Bull 44:2309-2313 (1996). Poorly water-soluble lipoates maybe included in a solid dispersion system with an enteric polymer such ashydroxypropylmethylcellulose phthalate and carboxymethylethylcellulose,and a non-enteric polymer, hydroxypropylmethylcellulose. See ToshiyaKai, et al., Oral Absorption Improvement of Poorly Soluble Drug UsingSoluble Dispersion Technique, Chem. Pharm. Bull. 44:568-571 (1996).Another solid dispersion dosage form include incorporation of the drugof interest with ethyl cellulose and stearic acid in different ratios.Kousuke Nakano, et al., Oral Sustained-Release Cisplatin Preparationsfor Rats and Mice, J. Pharm. Pharmacol. 49:485-490 (1997).

[0067] There are various methods commonly known for preparing soliddispersions. These include, but are not limited to the melting method,the solvent method and the melting-solvent method.

[0068] In the melting method, the physical mixture of a drug in awater-soluble carrier is heated directly until it melts. The meltedmixture is then cooled and solidified rapidly while rigorously stirred.The final solid mass is crushed, pulverized and sieved. Using thismethod a super saturation of a solute or drug in a system can often beobtained by quenching the melt rapidly from a high temperature. Undersuch conditions, the solute molecule may be arrested in solvent matrixby the instantaneous solidification process. A disadvantage is that manysubstances, either drugs or carriers, may decompose or evaporate duringthe fusion process at high temperatures. However, this evaporationproblem may be avoided if the physical mixture is heated in a sealedcontainer. Melting under a vacuum or blanket of an inert gas such asnitrogen may be employed to prevent oxidation of the drug or carrier.

[0069] The solvent method has been used in the preparation of solidsolutions or mixed crystals of organic or inorganic compounds. Solventmethod dispersions may prepared by dissolving a physical mixture of twosolid components in a common solvent, followed by evaporation of thesolvent. The main advantage of the solvent method is that thermaldecomposition of drugs or carriers may be prevented because of the lowtemperature required for the evaporation of organic solvents. However,some disadvantages associated with this method are the higher cost ofpreparation, the difficulty in completely removing liquid solvent, thepossible adverse effect of its supposedly negligible amount of thesolvent on the chemical stability of the drug.

[0070] Another method of producing solid dispersions is themelting-solvent method. It is possible to prepare solid dispersions byfirst dissolving a drug in a suitable liquid solvent and thenincorporating the solution directly into a melt of polyethylene glycol,obtainable below 70 degrees, without removing the liquid solvent. Theselected solvent or dissolved lipoate may be selected such that thesolution is not miscible with the melt of polyethylene glycol. Thepolymorphic form of the lipoate may then be precipitated in the melt.Such a unique method possesses the advantages of both the melting andsolvent methods. Win Loung Chiou, et al., Pharmaceutical Applications ofSolid Dispersion Systems, J. Pharm. Sci. 60:1281-1301 (1971).

[0071] Another controlled release dosage form is a complex between anion exchange resin and the lipoates. Ion exchange resin-drug complexeshave been used to formulate sustained-release products of acidic andbasic drugs. In one preferable embodiment, a polymeric film coating isprovided to the ion exchange resin-drug complex particles, making drugrelease from these particles diffusion controlled. See Y. Raghunathan etal., Sustained-released drug delivery system I: Coded ion-exchange resinsystems for phenylpropanolamine and other drugs, J. Pharm. Sciences 70:379-384 (1981).

[0072] Injectable micro spheres are another controlled release dosageform. Injectable micro spheres may be prepared by non-aqueous phaseseparation techniques, and spray-drying techniques. Micro spheres may beprepared using polylactic acid or copoly(lactic/glycolic acid).Shigeyuki Takada, Utilization of an Amorphous Form of a Water-SolubleGPIIb/IIIa Antagonist for Controlled Release From Biodegradable Microspheres, Pharm. Res. 14:1146-1150 (1997), and ethyl cellulose, YoshiyukiKoida, Studies on Dissolution Mechanism of Drugs from Ethyl CelluloseMicrocapsules, Chem. Pharm. Bull. 35:1538-1545 (1987).

[0073] Other controlled release technologies that may be used in thepractice of this invention are quite varied. They include SODAS, INDAS,IPDAS, MODAS, EFVAS, DUREDAS. SODAS are multi particulate dosage formsutilizing controlled release beads. INDAS are a family of drug deliverytechnologies designed to increase the solubility of poorly solubledrugs. IPDAS are multi particulate tablet formation utilizing acombination of high density controlled release beads and an immediaterelease granulate. MODAS are controlled release single unit dosageforms. Each tablet consists of an inner core surrounded by asemipermeable multiparous membrane that controls the rate of drugrelease. EFVAS is an effervescent drug absorption system. PRODAS is afamily of multi particulate formulations utilizing combinations ofimmediate release and controlled release mini-tablets. DUREDAS is abilayer tablet formulation providing dual release rates within the onedosage form. Although these dosage forms are known to one of skill,certain of these dosage forms will now be discussed in more detail.

[0074] INDAS was developed specifically to improve the solubility andabsorption characteristics of poorly water soluble drugs. Solubilityand, in particular, dissolution within the fluids of thegastrointestinal tract is a key factor in determining the overall oralbioavailability of poorly water soluble drug. By enhancing solubility,one can increase the overall bioavailability of a drug with resultingreductions in dosage. INDAS takes the form of a high energy matrixtablet, production of which is comprised of two distinct steps: theadensosine analog in question is converted to an amorphous form througha combination of energy, excipients, and unique processing procedures.

[0075] Once converted to the desirable physical form, the resultant highenergy complex may be stabilized by an absorption process that utilizesa novel polymer cross-linked technology to prevent recrystallization.The combination of the change in the physical state of the lipoatecoupled with the solubilizing characteristics of the excipients employedenhances the solubility of the lipoate.

[0076] The resulting absorbed amorphous drug complex granulate may beformulated with a gel-forming erodible tablet system to promotesubstantially smooth and continuous absorption.

[0077] IPDAS is a multi-particulate tablet technology that may enhancethe gastrointestinal tolerability of potential irritant and ulcerogenicdrugs. Intestinal protection is facilitated by the multi-particulatenature of the IPDAS formulation which promotes dispersion of an irritantlipoate throughout the gastrointestinal tract. Controlled releasecharacteristics of the individual beads may avoid high concentration ofdrug being both released locally and absorbed systemically. Thecombination of both approaches serves to minimize the potential harm ofthe lipoates with resultant benefits to patients.

[0078] IPDAS is composed of numerous high density controlled releasebeads. Each bead may be manufactured by a two step process that involvesthe initial production of a micromatrix with embedded lipoates and thesubsequent coating of this micromatrix with polymer solutions that forma rate limiting semipermeable membrane in vivo. Once an IPDAS tablet isingested, it may disintegrate and liberate the beads in the stomach.These beads may subsequently pass into the duodenum and along thegastrointestinal tract, preferably in a controlled and gradual manner,independent of the feeding state. Lipoate release occurs by diffusionprocess through the micromatrix and subsequently through the pores inthe rate controlling semipermeable membrane. The release rate from theIPDAS tablet may be customized to deliver a drug-specific absorptionprofile associated with optimized clinical benefit. Should a fast onsetof activity be necessary, immediate release granulate may be included inthe tablet. The tablet may be broken prior to administration, withoutsubstantially compromising drug release, if a reduced dose is requiredfor individual titration.

[0079] DUREDAS is a bilayer tableting technology that may be used in thepractice of the invention. DUREDAS was developed to provide for twodifferent release rates, or dual release of a drug from one dosage form.The term bilayer refers to two separate direct compression events thattake place during the tableting process. In a preferable embodiment, animmediate release granulate is first compressed, being followed by theaddition of a controlled release element which is then compressed ontothis initial tablet. This may give rise to the characteristic bilayerseen in the final dosage form.

[0080] The controlled release properties may be provided by acombination of hydrophilic polymers. In certain cases, a rapid releaseof the arginine α-ketoglutarate may be desirable in order to facilitatea fast onset of therapeutic affect. Hence one layer of the tablet may beformulated as an immediate release granulate. By contrast, the secondlayer of the tablet may release the drug in a controlled manner,preferably through the use of hydrophilic polymers. This controlledrelease may result from a combination of diffusion and erosion throughthe hydrophilic polymer matrix.

[0081] A further extension of DUREDAS technology is the production ofcontrolled release combination dosage forms. In this instance, twodifferent arginine α-ketoglutarate compounds may be incorporated intothe bilayer tablet and the release of drug from each layer controlled tomaximize therapeutic affect of the combination.

[0082] The arginine α-ketoglutarate of the invention can be incorporatedinto any one of the aforementioned controlled released dosage forms, orother conventional dosage forms. The amount of arginine α-ketoglutaratecontained in each dose can be adjusted to meet the needs of theindividual patient and the indication. One of skill in the art readingthis disclosure will readily recognize how to adjust the level ofarginine α-ketoglutarate and the release rates in a controlled releaseformulation, in order to optimize delivery of arginine α-ketoglutarateand its bioavailability.

THERAPEUTIC INDICATIONS

[0083] The controlled release arginine α-ketoglutarate formulations ofthe present invention can be used to obtain a wide range of desirableeffects. Further, the invention can be used in the treatment of diseaseswhich involve glutamate dehydrogenase deficiency, depressed prolylhydroxylase and lysyl hydroxylase activity. Further, the invention isuseful in the treatment of various adverse effects on the eyes and skinwhen the adverse effect are due to accumulation of protein glycation.Maintaining substantially constant levels of arginine α-ketoglutarateprovides a long term antioxidant effect which assists inimmunomodulation.

[0084] Because of the very minimal toxicity of arginine α-ketoglutarate,it can be given to a wide range of patients which have differentconditions from mild to serious without fear of adverse effects.Further, the controlled release formulations taught here are even saferthan quick release formulations in that serum levels obtained are lowcompared to quick release formulations.

[0085] The data provided here do not show specific treatments of many ofthe diseases or symptoms mentioned above. However, the invention isbelieved to be responsible for obtaining a wide range of beneficialeffects particularly when the controlled release formulation isadministered to patients over long periods of time, i.e., weeks, monthsand years. By maintaining substantially constant therapeutic levels ofarginine α-ketoglutarate in the blood over very long periods of time arange of desirable physiological results are obtained. Stateddifferently, by continually maintaining the constant therapeutic serumlevels of the powerful antioxidant and preventing protein glycation, thepathogenesis of atherosclerosis, cataracts and retinopathy is prevented.

EXAMPLES

[0086] With reference to Table 1, the following examples are put forthso as to provide those of ordinary skill in the art with a completedisclosure and description of how to make and use the present invention,and are not intended to limit the scope of what the inventors regard astheir invention nor are they intended to represent that the experimentsbelow are all or the only experiments performed. Efforts have been madeto ensure accuracy with respect to numbers used (e.g. amounts,temperature, etc.) but some experimental errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,molecular weight is weight average molecular weight, temperature is indegrees Centigrade, and pressure is at or near atmospheric.

[0087] Before formulating, a check should be made of the room andequipment in order to verify that the cleaning procedure has beenperformed and approved. Weigh and charge α-Arginine α-ketoglutarate andcalcium phosphate, then blend in Hobart at speed 1. Dissolve zein in 250mL of IPA and 50 mL of DW using the Silverson until sell dispersed.Granulate arginine with zein and blend at speed 1 for 15 minutes untilgranulate formed. Material should be light granulate, with yellow colorblended for 10-20 minutes. While mixing the zein granulate, suspendpectin in glycerin using Silveron. Pour the smooth pectin glycerinmixture into zein granulate and blend for 15-20 minutes. Finally,disperse the Stagaline-20 in 800 mL of 0.05M KH2PO4 at pH 6.8 untilsmooth free flowing material is obtained, then add this to granulate atspeed 2 and blend for 20 minutes. Continue the blending at speed 2 untilwell dispersed granulate is formed. After the material has beenthoroughly dried, place it through a fitzmill screen #093 with addedmagnesium stearate. Compress the material into tablets having a weightof 1500 mg with a fracture force of ±15 kg and with a disintegrationtime be >1 hour.

[0088] Table 1 is a data table showing the dissolution of a formulationof the invention which is a controlled release oral formulation ofarginine α-ketoglutarate over time with time shown in hours. TABLE 1Assay: Dissolution mg Arginine mg Arginine α-keto % of “Infinity”Timepoint Released/tab glutarate Released/tab Released 0.5 hr 90 16516.5 1 hr 138 254 25.5 2 hr 226 416 41.7 3 hr 308 566 56.8 4 hr 374 68869.0 5 hr 425 781 78.3 6 hr 467 859 86.2 7 hr 508 934 93.7 8 hr 538 98999.2 Infinity 542 997 100.0

[0089] Desired Tablet Wt.: 1500.0 mg Desired Batch Size: 1.0 kgIngredients Percent mg per Tablet kg per Batch 1. Arginine AKG 66.7 1000.0  0.667 2. Calcium Sulfate 17.3  259.5  0.173 3. Zein 1.3 19.50.013 4. Alginate (Satagiline) 3.3 49.5 0.033 5. Pectin 4.0 60.0 0.0406. Glycerin 6.7 100.5  0.067 7. Magnesium Stearate 0.7 10.5 0.007 Total100    1499.5  0.000

[0090] The instant invention is shown and described herein in what isconsidered to be the most practical, and preferred embodiments. It isrecognized, however, that departures may be made therefrom, which arewithin the scope of the invention, and that obvious modifications willoccur to one skilled in the art upon reading this disclosure.

[0091] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A controlled release oral dosage formulation,comprising: a therapeutically effective amount of arginineα-ketoglutarate; and an excipient material; wherein the formulation ischaracterized by releasing the arginine α-ketoglutarate in a manner soas to increase a period of time over which a therapeutic level ofarginine α-ketoglutarate is maintained as compared to a quick releaseformulation.
 2. The formulation of claim 1, wherein the releasing is ina manner which maintains the therapeutic level of arginineα-ketoglutarate for a period of time which is 10% or more longer ascompared to a quick release formulation.
 3. The formulation of claim 1,wherein the releasing is in a manner which maintains the therapeuticlevel of arginine α-ketoglutarate for a period of time which is 50% ormore longer as compared to a quick release formulation.
 4. Theformulation of claim 1, wherein the releasing is in a manner whichmaintains the therapeutic level of arginine α-ketoglutarate for a periodof time which is 100% or more longer as compared to a quick releaseformulation.
 5. The formulation of claim 1, wherein the releasing is ina manner which maintains the therapeutic level of arginineα-ketoglutarate for a period of time which is 200% or more longer ascompared to a quick release formulation.
 6. The formulation of claim 1,wherein the releasing is sufficiently slow that a maximum level ofarginine α-ketoglutarate obtained is less as compared to a maximum levelobtained with a quick release formulation.
 7. The formulation of claim1, wherein the releasing is sufficiently slow that a maximum level ofarginine α-ketoglutarate obtained is 50% or more, less as compared to amaximum level obtained with a quick release formulation.
 8. Theformulation of claim 1, wherein the releasing of arginineα-ketoglutarate is at a rate of about 25% or less per hour after aninitial release rate within 30 minutes following administration ascompared to a quick release formulation.
 9. The formulation of claim 1,wherein the releasing of arginine α-ketoglutarate is at a rate of about50% or less per hour after an initial release rate within 30 minutesfollowing administration as compared to a quick release formulation. 10.A method of treating a human patient, comprising: administering to ahuman patient a controlled release formulation of arginineα-ketoglutarate which formulation is characterized by maintaining atherapeutic level of arginine α-ketoglutarate in the patient'scirculatory system over a period of time greater than that obtained witha quick release formulation; and repeating the administering on three ormore consecutive days thereby maintaining a therapeutic level ofarginine α-ketoglutarate in the patient's circulatory system over atherapeutically effective period of time on three or more consecutivedays.
 11. The method of claim 10, wherein the therapeutic level ismaintained over a period of time which is 10% or more than that obtainedwith a quick release formulation and further wherein the repeating isover thirty or more consecutive days.
 12. The method of claim 10,wherein the therapeutic level is maintained over a period of time whichis 100% or more than that obtained with a quick release formulation andfurther wherein the repeating is over thirty or more consecutive days.13. The method of claim 12, wherein the therapeutic level is a levelsufficient to obtain measurable increase in prolyl hydroxylase and lysylhydroxylase activity in a human patient.
 14. The method of claim 12,wherein the therapeutic level is a level sufficient to prevent proteinglycation associated with atheroslerosis, cataract formation andretinopathy.